Peroxisome proliferators are a diverse group of chemicals that are of therapeutic, industrial and agricultural value and induce peroxisome proliferation in rodent and nonrodent species and hepatic tumors in rats and mice. Humans are continuously exposed to peroxisome proliferators and the controversy over the carcinogenic risk of peroxisome proliferators continues. It is well established that pleiotropic effects of peroxisome proliferators are mediated through peroxisome proliferator activated receptor (PPAR). However, the mechanism by which peroxisome proliferators induce liver tumors is not well understood and remains a controversial subject since these compounds are shown to be nongenotoxic in both in vitro and in vivo systems. Both peroxisome proliferator-induced oxidative stress and cell proliferation are implicated as the proximal cause of hepatocarcinogenesis. To evaluate the carcinogenic risk of peroxisome proliferators in humans it is essential to understand the exact mechanism of peroxisome proliferator- induced carcinogenesis in rodents. It is well known, that peroxisome proliferation is species specific, with rats, mice and hamsters being responsive and guinea pigs and primates considered to be nonresponsive species. Such species differences are not due to lack of PPAR, the principle mediator of peroxisome proliferator action. The peroxisome proliferative response is some what similar in rats, mice and hamsters, if not identical. Interestingly, however, liver tumors develop only in rats and mice but not in hamsters. Lack of tumor development in hamsters may be due to failure of peroxisome proliferators to cause cell proliferation, a factor considered to be risk factor for cancer development and/or considered to have a predictive value in evaluating the carcinogenecity of a chemical. Our objective is to investigate the reason(s) for such differences in rats and mice and hamsters in liver cell proliferation with the ultimate goal of identifying factors responsible for such differences. The specific aims of the present study are : 1) to examine for any differences in the expression and levels of fatty acid binding protein, a cytosolic protein considered specific mediator of peroxisome proliferator-induced mitogenesis, 2) quantitation of Kupffer cells, the source of tumor necrosis factor alpha, a potent hepatic mitogen, using Kupffer cell markers, 3) evaluate for expression of PPAR coactivators such as steroid receptor coactivator and PPAR- binding protein.